阅读说明：本技术 一种速崩型a群c群脑膜炎球菌多糖结合疫苗可溶性微针及其制备方法 (Rapidly disintegrating type A group C meningococcal polysaccharide conjugate vaccine soluble microneedle and preparation method thereof ) 是由 张庶民 马凤森 周荔葆 廖辉 陈中秋 刘苗苗 吴铮 辛小韵 于 2018-07-04 设计创作，主要内容包括：本发明提供了一种速崩型A群C群脑膜炎球菌多糖结合疫苗可溶性微针,所述的微针由聚乙烯吡咯烷酮、崩解剂、超细碳酸钙、A群C群脑膜炎球菌多糖结合疫苗组成；其中,崩解剂在针体中的固含量占比为6％～16％,超细碳酸钙在针体中的固含量占比为5％～20％,A群C群脑膜炎球菌多糖结合疫苗在针体中的固含量占比为不高于10％。本发明提供的可溶性微针,既提高了微针的释药速率,又避免了因快速释药导致的针体刺入皮肤效果差的技术缺陷；同时,免疫学实验结果证明该微针产生的免疫效果优于皮下注射,能有效的对机体产生免疫保护作用。(The invention provides a rapidly disintegrating type A group C meningococcal polysaccharide conjugate vaccine soluble microneedle, which consists of polyvinylpyrrolidone, a disintegrating agent, superfine calcium carbonate and A group C meningococcal polysaccharide conjugate vaccine; wherein, the solid content of the disintegrating agent in the needle body is 6-16%, the solid content of the superfine calcium carbonate in the needle body is 5-20%, and the solid content of the A group C meningococcal polysaccharide conjugate vaccine in the needle body is not higher than 10%. The soluble microneedle provided by the invention not only improves the drug release rate of the microneedle, but also avoids the technical defect of poor effect of penetrating a needle body into skin caused by rapid drug release; meanwhile, immunological experiment results prove that the microneedle has better immune effect than subcutaneous injection and can effectively generate immune protection effect on organisms.)

1. A rapidly disintegrating type soluble microneedle of a group A and group C meningococcal polysaccharide conjugate vaccine is characterized in that the microneedle consists of polyvinylpyrrolidone, a disintegrating agent, superfine calcium carbonate and a group A and group C meningococcal polysaccharide conjugate vaccine; wherein, the solid content of the disintegrating agent in the needle body is 6-16%, the solid content of the superfine calcium carbonate in the needle body is 5-20%, and the solid content of the A group C meningococcal polysaccharide conjugate vaccine in the needle body is not higher than 10%.

2. The rapidly disintegrating group A and group C meningococcal polysaccharide conjugate vaccine soluble microneedle according to claim 1, wherein the disintegrant is one or more selected from dry starch, sodium carboxymethyl starch, low-substituted cellulose, and croscarmellose sodium.

3. The rapidly disintegrating group a and group C meningococcal polysaccharide conjugate vaccine soluble microneedle according to claim 2, wherein the disintegrant is sodium carboxymethyl starch.

4. The rapidly disintegrating group A and group C meningococcal polysaccharide conjugate vaccine soluble microneedle according to any one of claims 1 to 3, wherein the solid content ratio of each component in the microneedle body is: 70% of polyvinylpyrrolidone, 10% of sodium carboxymethyl starch, 10% of superfine calcium carbonate and 10% of A group C meningococcal polysaccharide conjugate vaccine.

5. The method for preparing rapidly disintegrating group A and group C meningococcal polysaccharide conjugate vaccine soluble microneedles in any one of claims 1-3, wherein a dry powder compression molding method is adopted, and the method comprises the following steps: filling the materials with the prescription amount into a female die, punching and demoulding to obtain the flaky microneedle array.

Technical Field

The invention relates to the technical field of microneedle administration of vaccines, and provides a rapidly disintegrating type A group C meningococcal polysaccharide conjugate vaccine soluble microneedle and a preparation method thereof.

Background

Epidemic cerebrospinal meningitis is purulent meningitis caused by neisseria meningitidis, and is also called epidemic cerebrospinal meningitis. The clinical manifestations include fever, headache, vomiting, skin ecchymosis and stiffness of the neck, and the cerebrospinal fluid is purulent. The epidemic encephalitis vaccines on the market at present are injection preparations, the vaccines are mostly used for children, and the injection preparations have the defect of poor compliance. Therefore, a new administration route of vaccine is urgently needed. Human skin contains abundant antigen presenting cells, for example, Langerhans cells existing in epidermis account for 3-5% of all epidermal cells, so that transdermal immunity has a good research prospect. However, the stratum corneum barrier of the skin makes the delivery of macromolecular drugs problematic.

The soluble micro-needle belongs to a micro-needle type, can overcome the stratum corneum obstacle of human skin, can well promote the transdermal absorption of macromolecular antigen drugs, and realizes painless drug delivery. Different from other microneedles, the soluble microneedles can be dissolved automatically after penetrating into human skin, so that the problems of breakage of intradermal needles of the solid microneedles, small drug-loading amount of coated microneedles and the like are solved, and the method is a popular field for microneedle research at present.

Chinese patent publication No. CN107158368A discloses a soluble microneedle patch containing a polysaccharide conjugate vaccine and a method for preparing the same, which is described in paragraph [ 0042 ] of the document: the needle body of the micro-needle patch can release the target drug into the skin within 15-60 min; and the soluble microneedle body penetrating into the skin part can be ensured to be completely dissolved in the skin and release the A + C group epidemic cerebrospinal meningitis conjugate vaccine into the skin after 30 min. Therefore, when the patient is actually self-administered, the microneedle needs to be continuously pressed on the skin for 30min to be removed, which results in poor patient compliance.

Therefore, it is urgent to develop a soluble microneedle which can completely release the group a and group C meningococcal polysaccharide conjugate vaccine into the skin in a shorter time to overcome the poor patient compliance of the prior art.

At present, no patent document report that a disintegrating agent can be added into a soluble microneedle for quick release of a drug exists, and the applicant of the invention discovers in an earlier preliminary experiment that the disintegrating agent is difficult to effectively penetrate into the skin due to weak mechanical strength of a needle body while the rapid release of the microneedle is improved.

In conclusion, how to develop a rapidly disintegrating type A group C meningococcal polysaccharide conjugate vaccine soluble microneedle can improve the drug release rate of the microneedle after penetrating into the skin and solve the problem of patient compliance; but also can ensure enough mechanical strength to pierce the skin and even improve the immune response effect of the vaccine microneedle, which is a technical problem urgently needed to be solved by the technicians in the field.

Disclosure of Invention

The invention aims to provide a rapidly disintegrating type A group C meningococcal polysaccharide conjugate vaccine soluble microneedle and a preparation method thereof, and solves the bottleneck existing in the prior art by adding a disintegrating agent and superfine calcium carbonate in a proper proportion as a mechanical strength enhancing phase.

In order to realize the research and development thought, the technical scheme adopted by the invention is as follows:

a rapidly disintegrating A group C meningococcal polysaccharide conjugate vaccine soluble microneedle, which consists of polyvinylpyrrolidone, disintegrant, superfine calcium carbonate and A group C meningococcal polysaccharide conjugate vaccine; wherein, the solid content of the disintegrating agent in the needle body is 6-16%, the solid content of the superfine calcium carbonate in the needle body is 5-20%, and the solid content of the A group C meningococcal polysaccharide conjugate vaccine in the needle body is not higher than 10%.

Preferably, the disintegrating agent is selected from one or more of dry starch, sodium carboxymethyl starch, low-substituted cellulose and cross-linked sodium carboxymethyl cellulose,

more preferably, the disintegrant is sodium carboxymethyl starch.

Preferably, the solid content of each component in the needle body is as follows: 70% of PVP, 10% of sodium carboxymethyl starch, 10% of superfine calcium carbonate and 10% of group A and group C meningococcal polysaccharide conjugate vaccine.

The invention also provides a preparation method of the rapidly disintegrating group A and group C meningococcus polysaccharide conjugate vaccine soluble microneedle, namely a dry powder compression molding method is adopted, and the preparation method comprises the following steps: filling the materials with the prescription amount into a female die, punching and demoulding to obtain the flaky microneedle array.

In the invention, the superfine calcium carbonate is used as a mechanical strength enhancing phase, so that the mechanical strength of the microneedle can be greatly improved, and the skin puncture capability of the microneedle can be enhanced.

Compared with the prior art, the soluble microneedle patch of the rapidly disintegrating A-group and C-group meningococcal polysaccharide conjugate vaccine has the innovativeness that:

the microneedle adopts the technology of combining the disintegrant and the superfine calcium carbonate, improves the drug release rate of the microneedle (the drug is completely released within 3 min), and avoids the technical defect of poor effect of the needle body penetrating into the skin caused by rapid drug release; meanwhile, immunological experiment results prove that the microneedle has better immune effect than subcutaneous injection and can effectively generate immune protection effect on organisms.

Detailed Description

In order to make the technical solution of the present invention better understood by those skilled in the art, the technical solution in the present embodiment will be specifically described below. It should be noted that the following examples are only for illustrating the present invention and are not to be construed as limiting the present invention, and any modifications and changes made to the present invention within the spirit and scope of the claims are included in the scope of the present invention.